Abstract
Multiple sclerosis (MS) is a progressive autoimmune disease characterized by T-cell mediated demyelination in central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is a widely used in vivo disease model of MS. Glucocorticoids such as dexamethasone (dex) function as immunosuppressants and are commonly used to treat acute exacerbations of MS. Dex is also often used as a positive control in EAE studies, as it has been shown to promote motor behavior, inhibit immune cell infiltration into the CNS and regulate the activation of glial cell in EAE. This study further validated the effects of intravenously administrated dex by time-dependent fashion in EAE. Dex postponed clinical signs and motor defects in early stages of EAE. Histological analysis revealed that the degeneration of myelin and axons, as well as the infiltration of peripheral immune cells into the white matter of spinal cord was inhibited by dex in early stages of EAE. Additionally, dex-treatment delayed the neuroinflammatory activation of microglia and astrocytes. Furthermore, this study analyzed the expression of the neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor (MANF) in EAE, and the effect of treatment with dex on MANF-expression. We show that in dex-treated EAE mice expression MANF increased within myelinated areas of spinal cord white matter. We also show that intravenous administration with hMANF in EAE mice improved clinical signs and motor behavior in the early stage of EAE. Our report gives insight to the progression of EAE by providing a time-dependent analysis. Moreover, this study investigates the link between MANF and the EAE model, and shows that MANF is a potential drug candidate for MS.
Highlights
Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system (CNS)
We found that dex-treatment during EAE increased MANFpositive areas significantly in the white matter compared to the EAE + Veh group at 7 and 14 dpi, but this effect was progressively reduced at later time points (Figures 4A,B)
This study further showed that the intravenous administration of dex to MOG33−55/complete Freund’s adjuvant (CFA) induced mice postpones motor function loss in early stages of the disease
Summary
Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is one of the oldest neurological disease models in existence and is widely used to screen pharmacological compounds searching for drug candidates for MS MANF in Early-stage EAE of a target animal’s immune system against myelin via the injection of myelin components, such as myelin basic protein (MBP), proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein (MOG) (Ransohoff, 2012) This immunization results in a CD4+ T-cell driven inflammatory attack on the CNS, which induces paralytic demyelination. The most common model remains the C57BL/6 mouse EAE model, which features immunization with residues 35–55 of the MOG peptide emulsified in Freund’s adjuvant, combined with injections with pertussis toxin This results in a reproducible, monophasic disease course (Ransohoff, 2012). EAE models have in a few cases been used successfully in the preclinical development of MS therapeutics (Yednock et al, 1992; Brinkmann et al, 2002), but have generally been a poor predictor of drug efficiency (Steinman and Zamvil, 2006; Constantinescu et al, 2011; Lassmann and Bradl, 2017)
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